Abstract
Numerous studies have demonstrated a pathogenic association between rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM), 2 chronic inflammatory diseases. This study integrates transcriptomic and bioinformatic analyses to elucidate the shared molecular mechanisms underlying RA-associated T2DM, aiming to identify effective therapeutic strategies. RNA expression profile datasets for RA and T2DM were downloaded from the gene. Expression Omnibus and Gene Network (Grein) databases. Common differentially expressed genes shared between RA and T2DM were identified and subsequently subjected to gene enrichment analysis, protein-protein interaction network construction, GeneMANIA analysis, immune microenvironment evaluation, and drug prediction. Additionally, the diagnostic performance of hub genes was assessed using receiver operating characteristic curve analysis. Finally, molecular docking was employed to facilitate computer-aided drug design and to investigate drug-gene interactions. We identified 352 common differentially expressed genes, and functional analyses showed that they were mainly involved in the immune regulation of RA-associated T2DM. Thirteen key genes were confirmed through the protein-protein interaction network analysis and validation cohort. Receiver operating characteristic curves confirmed the reliability of their diagnostic value. GeneMANIA analyses suggested these genes were mainly associated with leukocytes, particularly neutrophils. Results from the immune microenvironment revealed abnormal levels of neutrophils in RA and T2DM. Among them, 10 key genes (LYN, TLR1, TLR2, TLR8, FCGR1A, FCGR2A, CCR1, CXCL1, FPR1, and SELL) were considered as neutrophil-related genes. Mechanistically, these genes activate pro-inflammatory signaling pathways, exacerbating tissue inflammation and promoting insulin resistance, ultimately leading to the onset of T2DM, neutrophils play a pivotal role in this process. Drug prediction and molecular docking results indicated that PD-169316 is a potential immunotherapeutic for patients with RA in combination with T2DM. This study concludes that neutrophil-driven inflammatory responses and their associated genes may accelerate the progression of type 2 diabetes caused by RA.